Connection between genetic variation and immune system, risk for neurodegenerative and other disease

Boston and Cambridge, MA - Researchers from Brigham and Women's Hospital (BWH), Harvard Medical School (HMS), the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and University of Chicago report findings demonstrating how genetic variations among healthy, young individuals can influence immune cell function. Many of those variants are also genetic risk factors for common diseases such as Alzheimer's disease, diabetes, and multiple sclerosis later in life, offering new insight into disease pathology.

The study will be published in the May 2, 2014 issue of Science.

"Over the last decade, geneticists have identified hundreds of genetic risk factors for several human diseases, but the functional consequences of those factors on relevant cells are largely unknown," said Towfique Raj, PhD, BWH Department of Neurology and a postdoctoral scholar at the Broad Institute, lead study author. "Our study highlights the potential role of immune system cells in human diseases."

The study was conducted as part of the ImmVar Project, which leveraged BWH's PhenoGenetic Project, a "living biobank" of healthy volunteers willing to contribute blood samples to understand how human genetic variations affect how the human body functions.

The researchers recruited a subset of 461 volunteers from the PhenoGenetic Project of African American, East Asian American, or European American ancestry. Two different types of immune cells--T cells and monocytes--were purified from each individual's blood, representing the adaptive and innate arms of immunity, respectively. The researchers profiled these cells to measure the expression of 19,114 genes in each cell type. They then examined genetic variants throughout the human genome for their effects on gene expression in these two representative populations of immune cells.

They discovered that genetic variation influencing a person's risk for multiple sclerosis, rheumatoid arthritis, and type 1diabetes is more likely to control gene activity in T cells than in monocytes. In contrast, genetic variation that increases one's risk for neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, shows a striking enrichment of functional effects in monocytes.

"This study shows that our genomes introduce changes in the immune system early on," said Christophe Benoist, MD, PhD, HMS, Broad Institute associate member, and study author. "These changes influence how a person responds to additional risk factors that he or she may encounter over the course of their life, making them more or less susceptible to triggering a disease process such as type 1, or juvenile, diabetes."

"The study focuses our attention on a particular part of the immune system that already exhibits changes caused by Alzheimer risk factors in people in their 20s and 30s," said Philip L. De Jager, MD, PhD, director, BWH Program in Translational NeuroPsychiatric Genomics, associate member at the Broad Institute, senior study author. "Functionally, we cannot say that blood-derived immune cells are the key cell type for Alzheimer's disease. They are likely to be proxies for the infiltrating and resident cells found at the sites of neuropathology. However, these exciting insights encourage us to explore how manipulating these immune cell types may one day slow or contribute to stopping the accumulation of Alzheimer's disease pathology that occurs as each of us ages."

By including volunteers of different genetic ancestries, the researchers also found that genetic variation that alters immune function is highly shared across human populations of different ancestry.

"Our multi-ethnic exploration of innate and adaptive immunity highlights a remarkable level of sharing across human populations of genetic variation influencing immune function, while identifying interesting instances of genetic effects on immune function that are specific to a population," said Nir Hacohen, PhD, MGH and the Broad Institute, study author.

"This study extends the narrative that many of the effects of disease-related genetic variation are specific to a certain context, such as a given immune cell type," said Barbara Stranger, PhD, University of Chicago, senior study author. "Thus, it is clear that further studies must investigate an increasingly complex matrix of cell types and conditions to fully understand the role of human genetic variation in disease."

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This research was supported by the United States National Institutes of General Medical Sciences (RC2 GM093080) and the National Institutes of Health (F32 AG043267).

About Brigham and Women's Hospital

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in Massachusetts and employs nearly 15,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information, resources and to follow us on social media, please visit BWH's online newsroom.

About the Broad Institute of MIT and Harvard

The Eli and Edythe L. Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.

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